Significant progress was made on this research project during this reporting period. 1) Despite extensive research, the neurobiological risk factors that convey vulnerability to opioid abuse are still unknown. Recent studies suggest that the dopamine D3 receptor (D3R) is involved in opioid self-administration, but it remains unclear whether altered D3R availability is a risk factor for the development of opioid abuse and addiction. To address this issue, we used D3R-KO mice and their wild-type littermates to study whether D3R loss alters heroin-taking and heroin-seeking behaviors in different stages of the drug addiction cycle. We found that D3R is critically involved in the regulatory processes that normally limit opioid intake. Deletion of D3R augments opioid-taking and opioid-seeking behaviors by a DA-dependent mechanism. Therefore, low D3R availability in the brain may represent a risk factor for the development of opioid abuse and addiction. 2) In addition to D3Rs, we have recently reported that mGluR2 is critically involved in the development of cocaine use and abuse. To further determine, whether low mGluR2 availability is also a risk factor in the development of opioid abuse, we used mGluR2-KO rats and their wild-type littermates as controls. We found that mGluR2-KO rats exhibited higher heroin self-administration and heroin intake, higher DA and locomotor responses to heroin, more potent morphine-induced analgesia and more severe naloxone-precipitated withdrawal symptoms, but lower motivation for heroin self-administration under high price progressive-ratio reinforcement conditions. These findings suggest that mGluR2 functionally plays an inhibitory role in opioid action. Deletion of this receptor results in an increase in brain DA responses to heroin and in acute opioid reward and analgesia. Thus, low-mGluR2 expression in the brain may therefore represent another risk factor for the initial development of opioid abuse and addiction. 3) In addition to D3R and mGluR2, recent human genetic associations assays suggest that a neuronal cell-adhesion molecule called receptor-type protein tyrosine phosphatase D (PTPRD) is also associated to cocaine abuse and addiction. To further characterize the role of this molecule in drug reward and addiction, we used PTPRD-KO mice and their WT littermates in cocaine self-administration experiments. We found that PTPRD-KO mice displayed robust reduction in cocaine self-administration and cocaine intake. Systemic administration of 7-BIA, a novel PTPRD inhibitor, dose-dependently reduced cocaine-conditioned place preference and cocaine self-administration. These results suggest that PTPRD could be another new a target in medication development for the treatment of cocaine use disorders (collaboration project). 4) In a recent article, we systemically reviewed recent progress of DA-based agonist therapies for cocaine use disorders based on lessons we learned from methadone and buprenorphine for the treatment of opioid use disorders.